Benzothiazine dioxides as anti-thromobotic agents

ABSTRACT

Certain 3,4-dihydro-4-oxo and 3-oxo-2H-1,2-benzothiazine-3carboxamide and 4-carboxamide 1,1-dioxide compounds effective in the treatment of thrombosis are disclosed.

Unite States Patent 1 Lombardino et a1.

1 1 BENZOTHIAZINE DIOXIDES AS ANTI-THROMOBOTIC AGENTS [75] Inventors:Joseph G. Lombardino; Edward A.

Wiseman, both of New London,

Conn.

[73] Assignee: Pfizer Inc., New York, NY.

[22] Filed: May 21, 1973 21 Appl. No.: 362,518

Related U.S. Application Data [63] Continuation-impart of Ser. No.114,037, Feb. 9, 1971, abandoned, which is a continuation of Ser. No.829,713, June 2, 1971, abandoned.

[52] U.S. C1. 424/246, 260/243 R [51] Int. Cl A6lk 27/00 Jan. 21, 1975Primary Examiner-Vincent D. Turner Attorney, Agent, or F irm-Connollyand Hutz [57] ABSTRACT Certain 3,4-dihydro-4-oxo and 3-ox0-2H-l,2-benzothiazine-3-carboxamide 'and 4-carboxamide 1,1- dioxide compoundseffective in the treatment of thrombosis are disclosed.

22 Claims, No Drawings BENZOTHIAZINE DIOXIDES AS ANTI-THROMOBOTIC AGENTSCROSS-REFERENCE TO RELATED APPLICATIONS The subject application is acontinuation-in-part of co-pending application Ser. No. 114,037, filedFeb. 9, 1971, now abandoned said application Ser. No. 1 14,037 in turnbeing a continuation of application Ser. No. 829,713, filed June 2,1969, and now abandoned.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION This inventiondiscloses a method for the treatment of thrombosis in animals, includinghumans, which comprises the administration to said animals and humans ofan effective dose of from 1 to 50 mg per day of a compound selected fromthe group consisting of those of the formulae:

and the base salts thereof with pharmacologically acceptable cations,wherein R is chosen from the group consisting of alkyl having from oneto three carbon atoms, phenyl, naphthyl, pyridyl, 3-methyl-2-pyridyl,4-methy1-2-pyridyl, S-methyI-Z-pyridyl, 6-methy1-2- pyridyl,-chloro-2-pyridyl, 5-bromo-2-pyridyl, 2- pyrazinyl, Z-pyrimidyl,4-pyrimidyl, 2-thiazolyl, 4-methyl-2-thiazolyl, 5'-bromo-2-thiazolyl,4,5-dimethyl-2-thiazolyl and mono and di-substituted phenyl wherein eachsubstituent is fluorine, bromine or chloscribed in US. Pat. No.3,591,584. Included within the scope of the designated compounds are thepharmaceutically-acceptable acid addition salts.

The products of this invention are tested in vitro for anti-thromboticactivity by measuring their activity as inhibitors of the aggregation ofrabbit, dog or human blood platelets induced by adenosine diphosphate orcollagen using techniques described by Constantine, J. W., Nature 214,1084 (1967) and by Born, G. V. R. and Cross, J. J. J., Journal ofPhysiology 168, 178 (1963 Sulfmpyrazone [1,2-diphenyl-4-( 2-phenylsulfinylethyl)-3,5-pyrazolidinedione] is known to inhibitcollagen-induced platelet aggregation, M. Packham et al., J. Exptl. Med.126, 171 (1967), and is adopted as an internal standard for comparingcompounds as inhibitors of collagen-induced blood platelet aggregation.

The compounds of this invention are tested in vivo on experimentalthrombosis in dogs using techniques similar to those described by Bornet al., British Journal of Experimental Pathology, 46, 569 (1965 or inNature, 22,761 (1964). Blood is withdrawn from treated dogs fordetermination of platelet counts and platelet responses to collagen andadenosine diphosphate.

Compounds of this invention are also tested in vivo in human volunteers.After drug administration, blood is withdrawn, and platelet responses tocollagen and adenosine diphosphate are compared with those of blooddrawn from human volunteer controls.

In accordance with a method of treatment of the present invention, theherein listed 3,4-dihydro-2H- l,2-benzothiazine-1,l-dioxideanti-thrombotic agents can be administered via the oral or parenteralroutes of For purposes of oral administration, tablets contain- I ingvarious excipients such as sodium citrate, calcium rine, alkoxy havingfrom one to three carbon atoms,

alkyl having from one to three carbon atoms or trifluoromethyl; R is amember selected from the group con sisting of hydrogen or alkyl havingfrom one to three carbon atoms. It is to be understood that many ofthese compounds exist in the enolic form (i.e. they are tautomeric andcan be 4-hydroxy or 3-hydroxy, as the case may be).

The methods of preparation and chemical properties of the benzothiazinedioxides of this invention are decarbonate and dicalcium phosphate maybe employed along with various disintegrants such as starch, alginicacid and certain complex silicates together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules; preferred materials would include lactose as well ashigh molecular weight polyethylene glycols. When aqueous suspensionsand- /or elixirs are desired for oral administration, the essentialactive ingredient therein may be combined with various sweetening orflavoring agents, coloring matter or dyes, and if desired, emulsifyingand/or suspending agents as well, together with such diluents as water,ethanol, propylene glycol, glycerin and various combinations thereof.

For purposes of parenteral administration, solutionsof these3,4-dihydro- 2H-1,2-benzothiazine-l,l-dioxides in sesame or peanut oilor in aqueous propylene glycol may be employed, as well as sterileaqueous solutions of the corresponding water-soluble alkali metal oralkaline-earth metal salts. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular solutions areespecially suitable for intravenous, intramuscular and subcutaneousinjection.

The following examples are given to more fully illustrate the invention.It is to be understood that these examples are for illustrative purposesonly and that the invention is not meant to be limited to the specificdetails of the examples.

EXAMPLE I The following in vitro evaluation is carried out according tothe methods developed by Constantine, J. W., Nature, 214, 1084 (1967)and Born, G. V. R. and Cross, J. J. 1., Journal of Physiology, 168, 178(1963). Anaesthetized male rabbits are bled from a carotid artery intoplastic centrifuge tubes containing 0.1 volume 3% sodium citrate.Platelet-rich plasma is separated by centrifugation at 100 G for minutesat C. Plasma from 3 animals is pooled; 5 ml samples are placed intoclear plastic cuvettes and stirred at 1000 rpm. The collagen is preparedby mincing tendon from freshly excised rabbit tendon with scissors,grinding with commercial sea sand and 0.154 M sodium chloride solutionby mortar and pestle to the consistency of coarse paste. After transferto an Erlenmemeyer flask, more sodium chloride solution is added ml per4 grams tendon). The mixture is shaken mechanically for about 60minutes, then centrifuged at 1,500 G for about 10 minutes. The collagensupernatant is added at about 0.25 to about 0.30 ml/4 ml plasmaimmediately after the addition of the drugs contained in 0.05 ml at aconcentration of 6 X 10' M. Changes in optical density are followed witha Spectronic 2O colorimeter attached to a Houston Instrument TYRecorder. Platelet aggregation is indicated by a decrease in opticaldensity. Inhibition to collagen-induced platelet aggregation isconsidered significant when this inhibition is approximately equal thatcaused by an equimolar concentration of sulfinpyrazone [1,2-diphenyl-4-(2-phenylsulfinylethyl)-3,5- pyrazolidinedione].

Test compounds which inhibit aggregation by collagen comparable with orbetter than sulfinpyrazone (i.e. 6 X 10 M) are indicated herein below:

4-ch1oro-3 ,4-dihydro-2-methyl-4-oxo-2H-1,2-benxothiazine-3-carboxanilide-l 1 -dioxide2-methoxy-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxanilide-1,l-dioxide 4-methoxy-3,4-dihydro-2-methyl-4-oxo-2H-1,2- benzothiazine-3-carboxanilide-l ,1-dioxide 2-methyl-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine-3-carboxanilide-1,l-dioxide4-methyl-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine-3-carboxanilide-1,l-dioxide3'-trifluoromethyl-3,4-dihydro-2-methyl-4-oxo-2l-l- 1,2-benzothiazine-3-carboxanilide-1 ,1 -dioxide 3-chloro-3,4-dihydro-2-methyl-4-oxo-2H- l ,2-benzothiazine-3-carboxanilidel 1 -dioxide 3',4-dichloro-3,4-dihydro-2-methyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxani1ide-1 ,l-dioxide 2 -chloro-3,4-dihydro-2-methyl-4-oxo-2H- l ,2- benzothiazine-3-carboxanilidell-dioxide 4'-nitro-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxanilide- 1 1 -dioxide4'-bromo-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxanilide-1,l-dioxide 3 '-methyl-3,4-dihydro2-methyl-4-oxo-2H-1 ,2- benzothiazine-3-carboxanilidel 1 -dioxide4'-ethoxy-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxanilide-l 1 -dioxideN-(a-naphthyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-cyclohexyl-3,4-dihydro-2-methyl-4-oxo-2l-l- 1,2benzothiazine-3-carboxamidel 1-dioxide N-allyl-3,4-dihydro-2-methy1-4-oxo-2H-1 ,2-benzothiazine-3-carboxamide-l 1 -dioxideN-methyl-3,4'dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxideN-(n-butyl)-3,4-dihydro-2-methyl-4oxo-1.2-benzothiazine-3-carboxamide-1,1-dioxide 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-thiocarboxanilide-1,l-dioxideN-allyl-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-thiocarboxanilide-1,l-dioxide3,4-dihydro-2-methyl-3-oxo-2H-l ,2benzothiazine-4-carboxanilide-1,l-dioxide 4-fluoro-3 ,4-dihydro-2-methyl-3-oxo-2H- l,2- benzothiazine-4-carboxanilide-1 1 -dioxide4'-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,l-dioxide 3-trif1uoromethyl-3,4-dihydro-2-methyl-3-oxo-2H- l,2-benzothiazine-4-carboxanilide-1,l-dioxide 4'-methyl-3,4-dihydro-2-methyl-3-oxo-2H-1,2- benzothiazine-4-carboxanilide-1 1-dioxide 4-methoxy-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,l-dioxide 4-nitro-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,l-dioxideN-(a-naphthyl)-3,4-dihydro-2-methyl-3oxo-2l-l-1,2-benzothiazine-4-carboxamide-1,1-dioxide3'-methyl-3,4-dihydro-2-methy1-3-oxo-2H- 1 ,2- 4benzothiazine-4-carboxanilide-1 1 -dioxide4-ethoxy-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-l ,l-dioxide 3 -chloro-3,4-dihydro-2-methyl-3-oxo-2l-l- 1 ,2- benzothiazine-4-carboxanilide-l 1-dioxide 2-methyl3 ,4-dihydro-2-methyl-3-oxo'2H-l ,2-benzothiazine-4-carboxanilide-1 1 -dioxide2,5'-dichloro-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,l-dioxide2'-methoxy-3,4-dihydro-2-methyl-3-oxo-2ll-1,2-benzothiazine-4-carboxanilide-1,l-dioxide 3',4-dichloro-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1 ,l-dioxide2'-methyl-4'-nitro-2,4-dihydro-2methyl-3=oxo-2H-1,2-benzothiazine-4-carboxanilide-1 1 -dioxide N-allyl-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,l-dioxide 3 '-trifluoromethyl-4-'-fluro-3,4-dihydro-2-methyl-3 oxo-l ,2-benzothiazine-4-carboxanilide-1 1-dioxide 2',4'-difluro-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,l-dioxide 2-fluoro-5 '-trifluromethyl-3,4-dihydro-2-methyl 3- oxo-ZH-l ,2-benZothiazine-4-carboxanilide-l ldioxide N-(3-hydroxy-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxamide-1,l-dioxide N-[ 3-( 6-phenyll,2,r-triazolyl ]-3,4-dihydro-2- methyl-4-oxo-2H-l ,2-benzothiazine-3-carboxamidel l -dioxide N-( 5-bromo-2-thiazolyl )-3,4-dihydro-2-methyl-4-oxo-ZH-l,2-benzothiazine-3-carboxamide-1,l-dioxide N-(5-carboxamide-2-pyridyl )-3 ,4-dihydro-2-methyl- 4-oxo-2H-l,2-benzothiazine- 3-carboxamide-l l -dioxide N-(4,5-dimethyl-2-thiazolyl )-3 ,4-dihydro-2-methyl-4-oxo-2l-l-1,Z-benzothiazine- 3-carboxamide-1 ,l-dioxideN-(4-chloro-2-benzothiazolyl)-3 ,4-dihydro-2- methyl-4oxo-2H-l,2-benzothiazine- 3-carboxamide-l 1 -dioxide N-(6-methyl-Z-benzothiazolyl )-3 ,4-dihydro-2- methyl-4-oxo-2l-l-l,Z-benzothiazine- 3-carboxamide-1 ,1 -dioxide N-(6-bromo-2-benzothiazolyl )-3 ,4-dihydro-2-methyl-4-oxo-2H-1,Z-benzothiazine- 3-carboxamide-1,l-dioxide N-(5-bromo-2-pyridyl )3 ,4-dihydro-2-methyl-4-oxo-21-14,2-benzothiazine-3-carboxamide-l,l-dioxide N-( 5-chloro-2-pyridyl)-3 ,4-dihydro-2-methyl-4-oxo- 2l-l-l ,2-benzothiazine-3-carboxamide-ll-dioxide N-( 4,6-dimethyl-2-pyrid yl )-3 ,4-dihydro-2-methyl-4-x0-2l-l-1,Z-benzothiazine-3-carboxamide-l,l-dioxide N-(-nitro-2-pyridyl)-3 ,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-l,l-dioxide N-( 5-methyl-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxamide-1,l-dioxide N-( 6-methyl-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo- 21-1-1 ,2-benzothiazine-3-carboxamide-1 1-dioxide N-(4-methyl-2-pyridyl )-3 ,4-dihydro-2-methyl-4-oxo- 2H-l,2-benzothiazine-3-carboxamide- 1 1 -dioxide N-( 3-methyl-2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,l-dioxide N-( 3-pyridyl )-3,4-dihydro-2-methyl-4-oxo-2H- l ,2- benzothiazine-3-carboxamidel l-dioxide N-(4-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine-3-carboxamide-l ,l-dioxide [N-2-( 5 -methyl-l ,3,4-thiadiazinyl )]-3 ,4-dihydro-2- methyl-4-oxo-2H-1,2-benzothiazine-l,l-dioxide N-( 5-chloro-2-benzoxazolyl )-3 ,4-dihydro-2-methyl-4-oxo-2l-l-1,2-benzothiazine- 3-carb0xamide-l ,l-dioxide N-( 2-thiazolyl)-4-hydroxy-2-methyl-2H-l ,2- benzothiazine-3-carboxamide-1,1-dioxide 2',4-dimethoxy-3 ,4-dihydro-2-methyl-3-oxo-2H-l,2-benzothiazine-4-carboxanilide-1,l-dioxide 4 -thiomethoxy-3,4-dihydro-2-methyl-3-oxo-2H-1 ,2- benzothiazine-4-carboxanilidel l-dioxide 3 '-choro-4 '-methyl-3 ,4-dihydro-2-methyl-3-oxo-2H-l,2-benzothiazine-4-carboxanilide-1 ,1 -dioxide 4 '-iodo-3,4-dihydro-2-methyl-3-oxo-2H-1 ,2- benzothiazine-4-carboxanilidel l-dioxide 4'-(n-butyl)-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilidel l -dioxideN-(n-amyl)-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxamidel l -dioxideN-cyclohexyl-3,4-dihydro-2-methyl-3-oxo-2l-l-1,2-benzothiazine-4-carboxamidel l -dioxide N-(B-phenylethyl)-3,4-dihydro-2-methyl-3-oxo-2H- l,2-benzothiazine-4-carboxamidel l-dioxide EXAMPLE ll Collagen-induced aggregation was inhibited withplatelets from each of three dogs treated orally with a single dose, 1mg/kg, of N-(2-thiazolyl)-4-hydroxy- 2-methyl-2H-1,2-benzothiazine-3-carboxamide-1 ,1- dioxide. This effect was evidentone hour following drug administration and persisted for about 96 hoursin two dogs and hours in the third.

N-(Z-thiazolyl)-4-hydroxy-2-methyl-2'H1,2- benzothiazi'ne-3-carboxamidel,l-dioxide, dissolved in 0.154 M NaCl, was administered intravenously todogs. Collagen-induced platelet aggregation was inhibited with plateletsfrom these dogs for up to 6 to 11 days after a single intravenousinjection of 2 mg, 5 mg or 10 mg/kg.

Similar results are obtained with the following compounds:

4'-bromo-3 ,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-l ,l-dioxide 3,4-dihydro-2-methyl-4-oxo-2H- l ,2-benzothiazine- 3-carboxanilide-l,l-dioxide N-( 2-thiazolyl)-4-hydroxy-2,4'-dimethyl-2H- l ,2-benzothiazine-3-carboxamide-1,l-dioxide4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1 ,2- benzothiazine-3-carboxamide-l,l-dioxide N-(4,5-dimethyl-2-thiazolyl)-4-hydroxy-2-methyl-2H-l,2-benzothiaZine-3-carboxamide-1,l-dioxide N-(6-methyl-2-pyridyl)-4-hydroxy-2-methyl-21-l-l ,2- benzothiazine-l 1-dioxide N-(4-methyl-2-pyridyl )-4-hydroxy-2-methyl-2H- l ,2-benzothiazine-3-carboxamidel 1 -dioxideN-(6-methyl-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,l-dioxideN-(5-chloro-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide EXAMPLE III A dry solidpharmaceutical composition is prepared by blending the followingmaterials together in the proportions by weight specified below:

benzothiazine-3-carboxamide-l ,l-dioxid'e 50 Calcium carbonate 20Polyethylene glycol, average molecular weight 4000 30 The dry solidmixture so prepared is then thoroughly agitated so as to obtain apowdered product that is completely uniform. Soft elastic and hardfilled gelatin capsules containing this pharmaceutical composition arethen prepared, employing a sufficient quantity of material in each caseso as to provide each capsule with 50 mg of the active ingredient.Similarly, the formula is modified so as to provide each capsule with 1mg of the active ingredient.

An oral dose of a single 50 mg capsule was administered to each of eighthuman volunteers. Collageninduced plately aggregation and release ofplatelet adenosine diphosphate were diminished in each of five subjectsat l, 2 and 6 hours after drug ingestion. Both responses, to a lesserextent, were still inhibited in these subjects at 24 hours. At 48 to 72hours after the single oral dose of the drug, the responses had returnedto control levels. In the sixth subject, collagen-induced plateletaggregation and release of platelet adenosine diphosphate werediminished at l and 2 hours after a single oral dose of 50 mg but not atlater intervals. In the remaining two subjects, both responses wereinhibited at 6 hours.

Collagen-induced plately aggregation and release of platelet adenosinediphosphate may be diminished by the administration of an oral dose of asingle capsule containing one mg of active ingredient.

What is claimed is:

l. A method for the treatment of thrombosis in dogs and humans whichcomprises the oral or intravenous administration to dogs and the oraladministration to humans both in need of such treatment of an effectivedose of from 1 to 50 mg per day of a compound selected from the groupconsisting of those of the formulae:

consisting of alkyl having from one to three carbon atoms, phenyl,naphthyl, pyridyl, 3-methyl-2-pyridyl,

4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2- pyridyl,5-chloro-2-pyridyl, S-bromo-Z-pyridyl, 2- pyrazinyl, 2-pyrimidyl,4-pyrimidyl, Z-thiazolyl,

4-methyl-2-thiazolyl, 5-bromo-2-thiazolyl, 4,5-dimethyl-2-thiazolyl andmono and di-substituted phenyl wherein each substitutent is fluorine,bromine, chlorine, alkoxy having from one to three carbon atoms ortrifluoromethyl; R is a member selected from the group consisting ofhydrogen and alkyl having from one to three carbon atoms.

2. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-2H-l ,2-benzothiazine-3-carboxamide-l ,l-dioxide wherein R is phenyl andR is alkyl having from one to three carbon atoms.

3. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-2H-l ,2-benzothiazine-3-carboxamide-l l -dioxide wherein R ischlorophenyl and R is alkyl having from one to three carbon atoms.

4. The method of claim 1 wherein said compound is a I 3,4-dihydro-4-oxo-ZH-l,2-benzothiazine-3-carboxamide-1,l-dioxide wherein R isdichlorophenyl and R is alkyl having from one to three carbon atoms.

5. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-2H-l ,2-benzothiazine-3-carboxamide-l ,l-dioxide wherein R is phenyl andR is hydrogen.

6. The method of claim 1 wherein said compound is a 3,4-dihydro-4 -oxo-2H-1,2-benzothiazine-3-carboxamide--l,l-dioxide wherein R is 2-thiazolyland R is alkyl having from.

one to three carbon atoms.

7. The method of claim 1 wherein said compound is a 3 ,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,l-dioxide wherein R is pyridyl andR is alkyl having from one to three carbon atoms.

8. The method of claim 1 wherein said compound is a 3,4-dihydro-4-oxo-Zl-l-l ,2-benzothiazine-3-carboxamide-l 1 -dioxide 10 wherein R ismethyl-Z-pyridyl and R is alkyl having from one to three carbon atoms.

9. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-2l-l-l ,2-benzothiazine-4-carboxamide-l ,1 -dioxide wherein R is phenyland R is alkyl having from one to three carbon atoms.

10. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-2H-l ,2-benzothiazine-4-carboxamide-l ,l-dioxide wherein R ischlorophenyl and R is alkyl having from one to three carbon atoms.

11. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-ZH-l ,2-benzothiazine-4-carboxamide-l ,l -dioxide wherein R is pyridyland R is alkyl having from one to three carbon atoms.

12. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-2H-l ,2-benzothiazine-4-carboxamide-l l -dioxide wherein R isbromophenyl and R is alkyl having from one to three carbon atoms.

13. The method of claim 1 wherein said compound is a 3,4-dihydro-3-oxo-ZH-l ,2-benzothiazine-4-carboxamide-l l -dioxide wherein R is naphthyland R is alkyl having from one to three carbon atoms.

14. The method of claim 1 wherein said compound is 3,4-dihydro-2-methyl-4-oxo-2H-l ,2-benzothiazine-3-carboxanilide-l ,1- dioxide.

15. The method of claim 1 wherein said compound is N-(2-thia'zolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-l,1-dioxide.

16. The method of claim 1 wherein said compound is 4'-bromo-3,4-dihydro-2-methyl-3-oxo-2H-l ,2-benzothiazine-4-carboxanilide- 1,1-dioxide.

17. The method of claim 1 wherein said compound is 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-l ,2-benzothiazine-3-carboxamide- 1,1-dioxide.

18. The method of claim 1 wherein said compound N-(4,5-dimethyl-2-,2-benzothiazine- 1S thiazolyl )-4-hydroxy-2-methyl-2H-l 3-carboxamide-ll -dioxide.

19. The method of claim 1 wherein said compound isN-(4-methyl-2-pyridyl)- 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxamide-l ,l-dioxide.

20. The method of claim 1 wherein said compound isN-(6-methyl-2-pyridyl)- 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxa-' mide-l,l-dioxide.

21. The method of claim 1 wherein said compound isN-(5-chloro-2-pyridyl)- 4-hydroxy-2-methyl-2H- 1,2-benzothiazine-3-carboxamide-l,l-dioxide.

22. The method of claim 1 wherein said compound 18N-(5-bromo-2-pyridyl)- 4-hydroxy-2-methyl-2l-l-l,2-benzothiazine-3-carboxamide-l 1 -dioxide.

2. The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is phenyl and R3 is alkyl having from one to three carbon atoms. 3.The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is chlorophenyl and R3 is alkyl having from one to three carbonatoms.
 4. The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is dichlorophenyl and R3 is alkyl having from one to three carbonatoms.
 5. The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is phenyl and R3 is hydrogen.
 6. The method of claim 1 wherein saidcompound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is 2-thiazolyl and R3 is alkyl having from one to three carbon atoms.7. The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is pyridyl and R3 is alkyl having from one to three carbon atoms. 8.The method of claim 1 wherein said compound is a3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide whereinR2 is methyl-2-pyridyl and R3 is alkyl having from one to three carbonatoms.
 9. The method of claim 1 wherein said compound is a3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide whereinR2 is phenyl and R3 is alkyl having from one to three carbon atoms. 10.The method of claim 1 wherein said compound is a3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide whereinR2 is chlorophenyl and R3 is alkyl having from one to three carbonatoms.
 11. The method of claim 1 wherein said compound is a3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide whereinR2 is pyridyl and R3 is alkyl having from one to three carbon atoms. 12.The method of claim 1 wherein said compound is a3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide whereinR2 is bromophenyl and R3 is alkyl having from one to three carbon atoms.13. The method of claim 1 wherein said compound is a3,4-dihydro-3-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxide whereinR2 is naphthyl and R3 is alkyl having from one to three carbon atoms.14. The method of claim 1 wherein said compound is3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxanilide-1,1-dioxide.15. The method of claim 1 wherein said compound isN-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
 16. The method of claim 1 wherein said compound is4''-bromo-3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxanilide-1,1-dioxide.17. The method of claim 1 wherein said compound is4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
 18. The method of claim 1 wherein said compound isN-(4,5-dimethyl-2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
 19. The method of claim 1 wherein saidcompound isN-(4-methyl-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.20. The method of claim 1 wherein said compound isN-(6-methyl-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.21. The method of claim 1 wherein said compound isN-(5-chloro-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.22. The method of claim 1 wherein said compound isN-(5-bromo-2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1, 1-dioxide.